PLGA: a unique polymer for drug delivery.

Biodegradable polymers have played an important role in the delivery of drugs in a controlled and targeted manner. Polylactic-co-glycolic acid (PLGA) is one of the extensively researched synthetic biodegradable polymers due to its favorable properties. It is also known as a 'Smart Polymer' due to its stimuli sensitive behavior. A wide range of PLGA-based drug delivery systems have been reported for the treatment or diagnosis of various diseases and disorders. The present review provides an overview of the chemistry, physicochemical properties, biodegradation behavior, evaluation parameters and applications of PLGA in drug delivery. Different drug-polymer combinations developed into drug delivery or carrier systems are enumerated and discussed.

Buccoadhesive films for once-a-day administration of rivastigmine: systematic formulation development and pharmacokinetic evaluation.

CONTEXT: Rivastigmine, an anti-Alzheimer's drug, suffers from major predicaments like low oral bioavailability, severe GI adverse effects related to rapid fluctuations in drug plasma levels, and high frequency of dosing. OBJECTIVE: The present investigation aims at developing buccoadhesive films capable of delivering the drug in vivo in a sustained manner. Augmentation of drug bioavailability by the avoidance of first-pass effect through the buccal route and reduction in GI side effects would be other key advantages of this system. METHODS: Buccoadhesive films of rivastigmine were systematically designed and evaluated for in vitro drug release, ex vivo buccal permeation and ex vivo buccoadhesive strength. Optimal composition of the polymer blends was rationally chosen using a central composite design and overlay plot. In vivo pharmacokinetic studies were carried out in rabbits, and attempts were made to establish in vitro/ in vivo correlations (IVIVC). RESULTS: Besides possessing the requisite drug release regulation, the optimized formulation exhibited excellent buccoadhesion, and buccal permeation. Pharmacokinetic studies indicated extension of plasma drug levels and level A of IVIVC was successfully established. DISCUSSION: Excellent buccal bioadhesion and transmucosal permeation, coupled with drug release control, ratify the potential of the optimized formulation to deliver the drug in a controlled and site-specific manner. Successful establishment of IVIVC substantiated the judicious choice of in vitro dissolution media for simulating the in vivo conditions. CONCLUSION: Besides unraveling the polymer synergism, the study helped in developing an optimal once-a-day buccoadhesive drug delivery system exhibiting excellent trans-buccal permeation and buccoadhesive characteristics with improved bioavailability potential.

Formulation, in vitro and in vivo evaluation of transdermal patches containing risperidone.

The efficacy of oral risperidone treatment in prevention of schizophrenia is well known. However, oral side effects and patient compliance is always a problem for schizophrenics. In this study, risperidone was formulated into matrix transdermal patches to overcome these problems. The formulation factors for such patches, including eudragit RL 100 and eudragit RS 100 as matrix forming polymers, olive oil, groundnut oil and jojoba oil in different concentrations as enhancers and amount of drug loaded were investigated. The transdermal patches containing risperidone were prepared by solvent casting method and characterized for physicochemical and in vitro permeation studies through excised rat skin. Among the tested preparations, formulations with 20% risperidone, 3:2 ERL 100 and ERS 100 as polymers, mixture of olive oil and jojoba oil as enhancer, exhibited greatest cumulative amount of drug permeated (1.87 ± 0.09 mg/cm(2)) in 72 h, so batch ROJ was concluded as optimized formulation and assessed for pharmacokinetic, pharmacodynamic and skin irritation potential. The pharmacokinetic characteristics of the optimized risperidone patch were determined using rabbits, while orally administered risperidone in solution was used for comparison. The calculated relative bioavailability of risperidone transdermal patch was 115.20% with prolonged release of drug. Neuroleptic efficacy of transdermal formulation was assessed by rota-rod and grip test in comparison with control and marketed oral formulations with no skin irritation. This suggests the transdermal application of risperidone holds promise for improved bioavailability and better management of schizophrenia in long-term basis.

Inclusion complex of aprepitant with cyclodextrin: evaluation of physico-chemical and pharmacokinetic properties.

OBJECTIVE: Aprepitant (APR) is a water insoluble drug approved for the treatment of chemotherapy induced nausea and vomiting (CINV) and post-operative nausea and vomiting (PONV). The innovator Emend® is a formulation incorporating drug nanoparticles with good bioavailability (~67%). The objective of the current work was to evaluate the feasibility of formulating a cyclodextrin complex of APR with enhanced solubility/dissolution rate and concomitantly bioavailability. METHODS: The complex was prepared using two approaches: kneading and slurry method. The formulated complex was evaluated using DSC, XRPD and FT-IR studies. RESULTS: DSC, XRPD and FT-IR studies confirmed the interaction of ß-cyclodextrin with APR indicating formation of a true complex wherein the drug was encapsulated in the cyclodextrin cavity (inclusion phenomenon). In addition to inclusion complexation, non inclusion phenomenon viz., interaction among hydroxyl groups of cyclodextrin and APR was also observed. The saturation solubility and dissolution rate of drug complex was higher than that of aprepitant API. The rate (C(max)) and extent of absorption (AUC) of APR from the complex were found to be comparable to that of Emend® (Reference product). CONCLUSION: These studies established that cyclodextrin complexation may provide another viable and cost effective option for enhancing solubility and bioavailability of APR.

Formulation, in vitro, and in vivo evaluation of matrix-type transdermal patches containing olanzapine.

Transdermal patches of olanzapine were aimed to be prepared to overcome the side effects by oral application. The strategy was formulation of eudragit-based polymeric films to prepare transdermal patches by using nonionic (span-20), anionic (sodium lauryl sulfate), cationic surfactant (benzalkonium chloride), and vegetable oil (olive oil) as permeation enhancers. The patches were subjected to physicochemical, in vitro release and ex vivo permeation studies. On the basis of in vitro release performance, ERL 100:ERS 100 in the ratio of 3:2 was selected for incorporation of permeation enhancers. The permeation studies showed that formulation containing 10% span 20 (OD3) exhibited greatest cumulative amount of drug permeated (19.02 ± 0.21 mg) in 72 h, so OD3 was concluded as optimized formulation and assessed for pharmacokinetic, pharmacodynamic, and skin irritation potential. In vivo studies of optimized olanzapine patch in rabbit model revealed prolongation of action with Frel 116.09% during 72-h study period. Neuroleptic efficacy of transdermal patch was comparable to oral formulation during rotarod and grip test in Wistar albino rats with no skin irritation. Thus, developed formulation of olanzapine is expected to improve the patient compliance, form better dosage regimen, and provide maintenance therapy to psychotic patients.

Propofol pharmacokinetics in young healthy Indian subjects.

OBJECTIVES: To analyze population pharmacokinetics of Propofol in Indian patients after single bolus dose of Propofol using WINNONLIN program. MATERIALS AND METHODS: Population pharmacokinetics of Propofol was investigated in Indian subjects in 26 elective surgical patients (14 males and 12 females) following single bolus dose of 2 mg/kg propofol. A total of 364 samples were estimated by High Performance Liquid Chromatography and pharmacokinetic parameters were derived using WINNONLIN (5.2). The effect of demographic characters of the study population on pharmacokinetic parameters was investigated. RESULTS: Three-compartment model was used to describe the pharmacokinetic data of Propofol in Indian subjects. Initial volume of distribution (V1) clearance (Cl) and steady state volume of distribution (Vd(ss)) was 13.5 ± 3.3 l, 1.08 ± 0.42 l/min, and 77.69 ± 48.0 l, respectively. Body weight best described the volume of central compartment (V1) as well as elimination clearance (P<0.01). CONCLUSION: Pharmacokinetics of Propofol in young healthy Indian subjects show lower volume of distribution and clearance as compared with most of the western data. Body weight best describes the V1, Vd(ss), and Clearance in this group.

In situ forming implant for controlled delivery of an anti-HIV fusion inhibitor.

An injectable, phase sensitive, in situ forming, implantable delivery system was developed for enfuvirtide, a therapeutic peptide used in the treatment of HIV infection. The development studies were carried out using poly (D,L-lactide-co-glycolide), a smart, biodegradable polymer. Different formulations were designed, prepared and evaluated by employing response surface, optimal design of experiment technique. The optimized formulation was identified and validated for its performance by using numerical optimization technique. The in vitro evaluation parameters included rheology, compatibility studies, drug release as well as conformational and physicochemical stability studies. In vivo pharmacokinetic parameters and biocompatibility studies were determined in rat models and were statistically analyzed. It was found that the optimized formulation extended the enfuvirtide release and maintained the drug plasma concentration within therapeutically effective range up to 48 h. The optimized formulation maintained physicochemical and conformational stability for at least 6 months and was biocompatible with the animal tissue.

Natural oils as skin permeation enhancers for transdermal delivery of olanzapine: in vitro and in vivo evaluation.

The feasibility of development of transdermal delivery system of olanzapine utilizing natural oils as permeation enhancers was investigated. Penetration enhancing potential of corn (maize) oil, groundnut oil and jojoba oil on in vitro permeation of olanzapine across rat skin was studied. The magnitude of flux enhancement factor with corn oil, groundnut oil and jojoba oil was 7.06, 5.31 and 1.9 respectively at 5mg/ml concentration in solvent system. On the basis of in vitro permeation studies, eudragit based matrix type transdermal patches of olanzapine were fabricated using optimized concentrations of natural oils as permeation enhancers. All transdermal patches were found to be uniform with respect to physical characteristics. The interaction studies carried out by comparing the results of ultraviolet, HPLC and FTIR analyses for the pure drug, polymers and mixture of drug and polymers indicated no chemical interaction between the drug and excipients. Corn oil containing unsaturated fatty acids was found to be promising natural permeation enhancer for transdermal delivery of olanzapine with greatest cumulative amount of drug permeated (1010.68 µg/cm²/h) up to 24 h and caused no skin irritation. The fabricated transdermal patches were found to be stable. The pharmacokinetic characteristics of the final optimized matrix patch (T2) were determined after transdermal application to rabbits. The calculated relative bioavailability of TDDS was 113.6 % as compared to oral administration of olanzapine. The therapeutic effectiveness of optimized transdermal system was confirmed by tranquillizing activity in rotarod and grip mice model.

Formulation development and systematic optimization of solid lipid nanoparticles of quercetin for improved brain delivery.

OBJECTIVE: This study aims at formulating solid lipid nanoparticles (SLNs) of quercetin, a natural flavonoid with established antioxidant activity, for intravenous administration in order to improve its permeation across the blood-brain barrier into the CNS, and eventually to improve the therapeutic efficacy of this molecule in Alzheimer's disease. METHODS: The SLNs of quercetin were formulated using Compritol as the lipid and Tween 80 as the surfactant through a microemulsification technique, and optimized employing a 3(2) central composite design (CCD). Selection of the optimized SLN formulation, using brute-force methodology and overlay plots, was based on its efficiency of entrapping quercetin inside the lipophilic core, particle size, surface charge potential and ability of the SLNs to release the entrapped drug completely. The optimized formulation was subjected to various in-vivo behavioral and biochemical studies in Wistar rats. KEY FINDINGS: The optimized formulation exhibited a particle size of less than 200 nm, 85.73% drug entrapment efficiency and a zeta potential of 21.05 mV. In all the in-vivo behavioral and biochemical experiments, the rats treated with SLN-encapsulated quercetin showed markedly better memory-retention vis-à-vis test and pure quercetin-treated rats. CONCLUSIONS: The studies demonstrated successful targeting of the potent natural antioxidant, quercetin, to brain as a novel strategy having significant therapeutic potential to treat Alzheimer's disease.

Design and development of paclitaxel-loaded bovine serum albumin nanoparticles for brain targeting.

Bovine serum albumin (BSA) nanoparticles loaded with paclitaxel (PTX) were prepared using a desolvation technique. A 32 full factorial design (FFD) was employed to formulate nanoparticles. Nanoparticles were characterized for particle size by photon correlation spectroscopy and surface morphology by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Encapsulation efficiency, zeta potential and particle yield were also determined. Response surface linear modelling (RSLM) was used to predict the optimal formulation. Various models were applied to determine the release mechanism from PTX nanoparticles. The effect of drug-polymer ratio on the release profile of formulations was observed and was applied to determine the suitability of the predicted optimal formulation. A preliminary study to determine the feasibility of targeting the prepared nanoparticles to brain was also carried out using mice as in vivo models.

Development and evaluation of in situ gel-forming system for sustained delivery of insulin.

Phase-sensitive in situ gel-forming controlled release formulations of insulin were prepared using poly(lactide-co-glycolide) and a solvent system consisting of various proportions of benzyl benzoate and benzyl alcohol. The in vitro release samples of formulations were assayed for insulin content by enzyme linked immunosorbent assay. Sodium dodecyl sulfate polyacrylamide gel electrophoresis and circular dichroism spectroscopy studies of released insulin confirmed its conformational stability. The stability of insulin in the formulation was assessed using Fourier transform infrared spectroscopy. Rheological properties of the formulations, assessed under isothermal conditions, showed dilatant behavior of all the formulations. In vivo studies were carried out on the optimized formulations vis-à-vis pure insulin in mice and blood glucose levels were monitored for 15 days. Mean percentage reduction in blood glucose levels was calculated in all the animals and the results analyzed using ANOVA. The studies construed better pharmacodynamic response for the two optimized formulations in controlling the blood glucose levels vis-à-vis routine once-a-day administration of insulin. The subcutaneous tissues, further subjected to scanning electron microscopy studies and histopathological examinations, ascertained the biocompatibility of the formulation.

Flow, compressive, and bioadhesive properties of various blends of poly(ethylene oxide).

BACKGROUND: Poly (ethylene oxide) (PEO) is nonionic, water soluble, and highly hydrophilic polymer with well-established applications in mucoadhesives, water-soluble films, rheology control agents and thickeners, and additives in pharmaceutical products. METHODS: Different powder blends containing PEO in varying proportions were evaluated for their flow, compressive, and bioadhesive properties and subsequently compressed into gastroretentive tablets. Two optimized formulations, on the basis of above-mentioned examinations, were subjected to gamma scintigraphy studies on human volunteers. RESULTS: The values of bulk and tapped densities, Hausner ratio and Carr index, angle of repose, loss on drying, total moisture content, and particle size distribution provided a fine estimation of flowability and compressibility of the powder blends. Further, apart from the routine pharmacopoeial assessments, the evaluation of compressed tablets for their surface pH in both acidic and basic environments nullified the possibility of any irritation to the membrane where it is intended to adhere. The measurement of swelling index and bioadhesive strength of tablets revealed that both the parameters were a direct function of the concentration of PEO in the tablet. The results of gamma scintigraphy indicated a fourfold increase in the gastric retention time of the optimized formulation vis-à-vis control formulation. CONCLUSION: The results indicate that PEO, in a concentration of 10-50% (w/w), can be successfully employed in manufacturing gastroretentive tablets.

Development and evaluation of in situ gel forming system for sustained delivery of cyclosporine.

Phase-sensitive in situ gel forming controlled release formulations of cyclosporine were prepared using poly (lactide-co-glycolide) and a solvent system consisting of various proportions of benzyl benzoate and benzyl alcohol. Uniformity of content of cyclosporine in the formulation and in vitro release samples was determined by radio immune assay (RIA). FTIR and CD spectroscopy ratified the conformational stability of cyclosporine in the formulation and in vitro release samples, respectively. Rheological properties of the formulations, assessed under isothermal conditions, showed dilatant behavior of all the formulations. In vivo studies were carried out on the optimized formulations vis-à-vis pure cyclosporine in rats and drug levels were monitored for 13 days. Mean plasma concentration of cyclosporine was calculated for all the animals and pharmacokinetic parameters were determined using Win NonLin software. The studies construed better regulation of plasma drug levels with the optimized formulation vis-à-vis routine once-a-day administration of cyclosporine. The subcutaneous tissues, further subjected to histopathological examinations ascertained the biocompatibility of the formulation.

Prednisolone-loaded albumin nanospheres: in vitro and in vivo evaluation studies.

Prednisolone-loaded bovine serum albumin (BSA) nanospheres prepared by pH-coacervation were evaluated regarding recovery, drug entrapment efficiency, particle size, shape, surface morphology, in vitro drug release profile, and in vivo distribution. The method of analysis was validated in terms of accuracy, precision, and repeatability. No significant change in the drug's chemical integrity was observed when incorporated in the nanospheres. It was observed that the average particle size and drug entrapment efficiency of the nanospheres increased with the increase in drug loading. All the batches exhibited biphasic drug release with an initial burst effect followed by gradual steady release. The higher the drug loading, the greater was the burst effect. The mechanism of prednisolone release from the nanospheres was found to be due to diffusion and erosion as observed by fitting the release data in different models. The drug's in vivo distribution was found to be highest in the liver followed by the spleen and lungs. Stability studies indicated that nanosphere formulations should be stored at 4 +/- 2 degrees C.

Nonsurgical approaches for the treatment of anal fissures.

Chronic anal fissure (CAF) is usually associated with internal anal sphincter spasm, the relief of which is central to provide fissure healing. The treatment for CAF has undergone a transformation in recent years from surgical to medical. Both the approaches share the common goal of reducing the spasm. Though surgical treatment has a high success rate, it can permanently impair fecal continence in a large number of patients. Smooth muscle relaxation seems to be a novel way by which more than 60% of the patients can be cured with the topical use of the agents. This treatment is in addition to the normalization of stools mostly. Smooth muscle relaxation is well tolerated, can be administered on an outpatient basis, does not cause any lesion of the continence organ, and subsequently, does not lead to any permanent latent or apparent fecal incontinence. This review encompasses various agents that are used for smooth muscle relaxation. In addition, it describes various clinical studies reported in the literature with their success rates and side effects.

Bioavailability of immediate- and extended-release formulations of glipizide in healthy male volunteers.

BACKGROUND AND OBJECTIVE: An extended-release glipizide formulation using a hydrophilic matrix system containing hydrophilic polymers has been developed for use in diabetes mellitus. This study compared the pharmacokinetic parameters of immediate- and extended-release formulations of glipizide 5mg in healthy male volunteers. METHODS: In a single-dose, four-period, four-treatment, Latin-square crossover study, the bioavailability of immediate-release glipizide 5mg (Glynase) [GL], extended-release glipizide 5mg (Glynase) XL [GLXL], Glucotrol XL [GTXL], and the new formulation developed in our laboratory [GLPF]) was compared. Plasma glipizide levels of the four formulations were determined at different time intervals, and pharmacokinetic parameters were analysed using a two-compartment body model. RESULTS: The mean peak plasma concentration (C(max)) of the immediate-release formulation (523+/-60 ng/mL) was significantly higher (p<0.05) than those of the three extended-release formulations (403+/-24, 349+/-37 and 426+/-55 ng/mL for GLXL, GTXL and GLPF, respectively). Mean time to reach C(max) was 1.83+/-0.3 hours for GL, 4.41+/-1.2 hours for GLXL, 3.21+/-0.8 hours for GTXL and 3.24+/-0.4 hours for GLPF. The order of magnitude of area under the plasma concentration-time curve was GTXL (5591 ng . h/mL)>GLXL (4,771 ng . h/mL)>GLPF (4,537 ng . h/mL)>GL (1,897 ng . h/mL). The mean residence time was 3.14+/-0.59 hours for GL, 8.26+/-0.81 hours for GLXL, 9.70+/-2.70 hours for GTXL and 7.87+/-1.93 hours for GLPF. Extended-release glipizide formulations maintained effective plasma drug concentrations for approximately 24 hours. Plasma levels of glipizide fluctuated less with GTXL than with the other two extended-release formulations. CONCLUSION: The newly developed formulation (GLPF) maintained effective levels of glipizide for a period of more than 20 hours, with quicker onset of action than the other two formulations. This formulation may be more economical than glipizide GITS.

Passiflora: a review update.

This review describes the morphology, microscopy, traditional and folklore uses, phyto-constituents, pharmacological reports, clinical applications and toxicological reports of the prominent species of the genus Passiflora. Flavonoids, glycosides, alkaloids, phenolic compounds and volatile constituents have been reported as the major phyto-constituents of the Passiflora species. A few species of Passiflora have been used for curing various ailments, the most important being Passiflora incarnata Linneaus which possesses significant CNS depressant properties. The studies performed by the authors with the newly isolated benzoflavone (BZF) moiety from P. incarnata have been discussed. In the concluding part, various virgin areas of research on the species of this genus have been highlighted with a view to explore, isolate and identify the medicinally important phyto-constituents which could be utilized to alleviate various diseases affecting the mankind.

Evaluation of mucoadhesive properties of chitosan microspheres prepared by different methods.

The mucoadhesive properties of chitosan microspheres prepared by different methods were evaluated by studying the interaction between mucin and microspheres in aqueous solution. The interaction was determined by the measurement of mucin adsorbed on the microspheres. A strong interaction between chitosan microspheres and mucin was detected. The intensity of the interaction was dependent upon the method of preparation of chitosan microspheres and the amount of mucin added. The extent of mucus adsorption was proportional to the absolute values of the positive zeta potential of chitosan microspheres. The zeta potential in turn was found to be dependent upon the method of preparation of microspheres. The adsorption of type III mucin (1% sialic acid content) was interpreted using Freundlich or Langmuir adsorption isotherms. The values of r2 were greater for Langmuir isotherm as compared with Freundlich isotherm. The adsorption of a suspension of chitosan microspheres in the rat small intestine indicated that chitosan microspheres prepared by tripolyphosphate cross-linking and emulsification ionotropic gelation can be used as an excellent mucoadhesive delivery system. The microspheres prepared by glutaraldehyde and thermal cross-linking showed good stability in HCl as compared with microspheres prepared by tripolyphosphate and emulsification ionotropic gelation.

Attenuation of benzodiazepine dependence in mice by a tri-substituted benzoflavone moiety of Passiflora incarnata Linneaus: a non-habit forming anxiolytic.

PURPOSE: A tri-substituted benzoflavone moiety (BZF) recently isolated from the methanol extract of aerial parts of the plant Passiflora incarnata Linneaus had exhibited encouraging results in countering the dependence produced by addiction-prone substances like morphine, nicotine, cannabinoids and ethyl alcohol, during the studies performed by the authors. Since the BZF moiety had exhibited significant anxiolytic properties at 10 mg/kg p.o. dose in mice, therefore, it was desirable to evaluate this potential phyto-moiety (BZF) for its own dependence-liabilities It was also deemed viable to evaluate BZF moiety for its possible usefulness in countering the dependence-liabilities associated with the chronic use of benzodiazepines keeping in light their tremendous clinical use in the management of anxiety and insomnia. METHODS: Different groups of mice were administered BZF alone (10, 50 or 100 mg/kg, p.o.), and concomitantly with diazepam (20 mg/kg, p.o.) in a 21-days treatment regimen, followed by no treatments for the next 72-hours. The withdrawal effects in the form of ambulatory behavior of the treated animals were recorded on the 25th day using an Actophotometer. RESULTS: The BZF-alone (three doses) treated mice exhibited a normal ambulatory behavior on 25th day. Mice groups receiving co-treatments, i.e., BZF-diazepam concomitantly, also exhibited a normal ambulatory behavior in a dose-dependent manner, i.e., the higher dose of BZF (100 mg/kg) being more effective in countering the withdrawal effects of chronically administered diazepam than the lower doses (10 or 50 mg/kg). CONCLUSIONS: The studies revealed that the chronic administration of the BZF moiety (three doses), did not exhibit any dependence-liability of its own, even upon an abrupt cessation. Additionally, the BZF co-treatments with diazepam also prevented the incurrence of diazepam-dependence, which might be because of the aromatase enzyme inhibiting properties associated with the BZF moiety.